Lung Cancer Master Protocol Activation Announcement Jeff Allen, PhD - PowerPoint PPT Presentation

Lung Cancer Master Protocol Activation Announcement

Jeff Allen, PhD Friends of Cancer Research

Panelists • Jeff Allen, PhD , Friends of Cancer Research • Roy Herbst, MD, PhD, Yale Cancer Center • David Gandara, MD, UC Davis Cancer Center • Vali Papadimitrakopoulou, MD , MD Anderson Cancer Center • Ann Ashby, MBA, Foundation for the NIH • Vince Miller, MD, Foundation Medicine • Jeff Abrams, MD, Clinical Investigations Branch, NCI • Janet Woodcock, MD, CDER, FDA • Mary Redman, PhD, Fred Hutchinson Cancer Center

Roy Herbst, MD, PhD Yale Cancer Center

Governance Structure: S1400 Master Lung-1 Project

Multi-Sector Oversight Committee Name Affiliation Roy Herbst (co-chair) Yale Cancer Center Ellen Sigal (co-chair) Friends of Cancer Research Jeff Abrams NCI Jeff Allen Friends of Cancer Research David Chang Amgen Andrea Ferris LUNGevity David Gandara UC Davis Cancer Center Rich Gaynor Eli Lilly Fred Hirsch University of Colorado Cancer Center Pasi Janne Dana Farber Cancer Institute Vali Papadimitrakopoulou MD Anderson Cancer Center Eric Rubin Merck Regina Vidaver National Lung Cancer Partnership Jack Welch NCI Janet Woodcock CDER, FDA Steven Young Addario Lung Cancer Medical Institute (ALCMI)

Drug Selection Committee VOTING Members Roy Herbst (chair) , Yale Cancer Center Gary Kelloff, NCI Kathy Albain, Loyola Medicine Vali Papadimitrakopoulou, MD Anderson • • Jeff Bradley , Washington University in St. Louis Suresh Ramalingam , Emory Healthcare Jeff Allen, Friends of Cancer Research Mary Redman, Fred Hutchinson Cancer Center • • Matt Hawryluk, Foundation Medicine Ellen Sigal, Friends of Cancer Research Kapil Dhingra, KAPital Consulting David Rimm, Yale Cancer Center • • Pat Keegan, FDA Caroline Sigman, CCS Associates Gwen Fyfe, Consultant Mark Socinski, UPMC Cancer Center • • Liz Mansfield, FDA David Wholley, FNIH David Gandara , UC Davis Cancer Center Naoko Takebe, NCI • • Shakun Malik, FDA Roman Yelensky, Foundation Medicine Glenwood Goss , University of Ottawa Everett Vokes , University of Chicago • Vince Miller, Foundation Medicine Jack Welch, NCI Fred Hirsch , University of Colorado Cancer Center Non- Voting Members Peter Ho, QI Oncology Ignacio Wistuba , MD Anderson Pasi Janne , Dana Farber Cancer Institute Jamie Zwiebel, NCI Non-Voting Members Jeff Allen, Friends of Cancer Research Mary Redman, Fred Hutchinson Cancer Center Matt Hawryluk, Foundation Medicine Ellen Sigal, Friends of Cancer Research Shakun Malik, FDA David Wholley, FNIH Vince Miller, Foundation Medicine Roman Yelensky, Foundation Medicine

David Gandara, MD University of California Davis Comprehensive Cancer Center

Master Lung Protocol (S1400): Addressing unmet needs in NSCLC David R. Gandara, MD University of California Davis Comprehensive Cancer Center

“Strategies for Integrating Biomarkers into Clinical Development of New Therapies for Lung Cancer” A Joint NCI Thoracic Malignancies Steering Committee-FDA Workshop Bethesda MD – February 2-3, 2012 • Trial Design Challenges in the Era of Biomarker-driven Trials • Innovative Statistical Designs • Challenges for Community Oncology Practice participation • The Patient Perspective • Drug & Biomarker Co-Development in Lung Cancer • Failure of “All Comer” designs for drug development in NSCLC • Need for Early Co-Development of drugs & associated biomarkers • Development of Future Lung Cancer Clinical Trials • TMSC Master Protocol Task Force in NSCLC • Biomarker-driven trial designs in both early stage adjuvant therapy & advanced stage NSCLC • Account for inter-patient tumor heterogeneity & genomic complexity of NSCLC

Classic RCT Design (“All Comer”): Phase III Trials of Chemotherapy +/- Targeted Agent* in 1 st -line Therapy of Advanced Stage NSCLC Target Agent Survival Benefit MMPs Prinomastat, Others No EGFR TKI Gefitinib or Erlotinib No Farnesyl Transferase (RAS) Lonafarnib No PKC α ISIS 3521 No RXR Bexarotene No VEGFR (TKI) Sorafenib No VEGF (Mab) Bevacizumab Yes EGFR (Mab) Panitumumab No TLR9 Agonist PF-351 No EGFR (Mab) Cetuximab Yes** IGFR-1 Figitumumab No VDA ASA-404 No *In combination with platinum-based chemotherapy versus chemotherapy Need for a completely “New Way of Thinking” for development of **EGFR IHC positive Targeted Drug/Biomarker Combinations: “Master Protocol” from Gandara et al: Clin Lung Cancer, 2012

Integrated New Drug-New Biomarker Development Paradigm: from Gandara et al: Clin Lung Cancer, 2012

Strategies for integrating Biomarkers into Clinical Trial Designs for NSCLC when viewed as a Multitude of Genomic Subsets Evolution of NSCLC  Histologic Subsets  Genomic Subsets Unmet needs addressed by Master Protocol: • How to develop drugs for uncommon-rare genotypes? • How to apply broad-based screening (NGS)? • How to achieve acceptable turn- around times for molecular testing for therapy initiation? (<2 weeks) • How to expedite the new drug- biomarker FDA approval process? (companion diagnostic) Li, Mack, Kung, Gandara: JCO 2013

Parallel Efforts in “Master Protocol” Design for NSCLC Friends of Cancer NCI Thoracic Malignancy Research (FOCR) Steering Committee Task Force (TMSC) Task Force • Early Stage NSCLC • Advanced Stage NSCLC (ALCHEMIST) • Squamous (SCCA): • Advanced Stage NSCLC SWOG • Non-Squamous SCCA represents an Unmet Need • • Non-Squamous All recent new targeted therapies have been in Adenoca (EGFR/ALK) • Many new molecular targets have been found in lung SCCA • Drugs for each of these targets

S1400 Master Protocol Unique Private-Public Partnerships with the NCTN Alliance ECOG- SWOG National Acrin S1400 Clinical Trials Master Network Protocol NCI-C NRG

Vali Papadimitrakopoulou, MD MD Anderson Cancer Center

Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer (SCCA) Study Chair: Vali Papadimitrakopoulou, MD UT/MDACC, Dept of Thoracic/Head & Neck Med Oncology Cooperative Groups Co-chairs: Alliance: Everett Vokes, MD ECOG: Suresh Ramalingam, MD NCI Co-Chair: Jack Welch, MD NCIC: Glenwood Goss, MD NRG: Jeff Bradley, MD SWOG: David R. Gandara, MD Steering Committee Co-Chair: Roy S. Herbst, MD, PhD Statistical Co-chair: Mary W. Redman, Ph.D. Molecular Pathology co-Chair: Ignacio Wistuba, MD Correlative Science co-Chair: F Hirsch MD, PhD, P Mack PhD

Rationale for Master Protocol Designs • NSCLC: multiple and often independent mutations and potential therapeutic targets. • Lung SCCA “orphan” group- substantial developments in therapeutics have yet to be seen. • Subgroup selection (genotype or phenotype-driven) refined strategy in a Multi-arm Master Protocol with improved operational efficiency: homogeneous patient populations & consistency in eligibility from arm to arm. Phase II- III design: rapid drug/biomarker testing for detection of “large effects” • Grouping multiple studies: reduces overall screen failure rate , multi-target screening by NGS platform: sufficient “hit rate” uninterrupted accrual. • Bring safe and effective drugs to patients faster, ineffective drugs are replaced by new improved candidates. • Designed to allow FDA approval of new therapeutics.

Significantly mutated genes in lung SQCC. PS Hammerman et al. Nature 000 , 1-7 (2012) doi:10.1038/nature11404

Assumptions, Major Elements and Objectives • Each drug clinical data demonstrating biologic activity in a responsive patient group against a measurable target, using predictive biomarker assay that has been analytically validated and is suitable for a pivotal trial. • Squamous cell carcinoma (SCCA), advanced stage, 2 nd line therapy • Multi-arm randomized, controlled phase II/III registration protocol. Each arm opens/closes independent of other arms, independently powered for OS. Positive results at “rolling” interim analysis determine if a protocol arm proceeds to phase III portion. • Primary Objectives: • A) Phase II Component: PFS targeted therapy (TT) vs SOC • B) Phase III Component : OS for TT vs SOC within each biomarker-defined subgroup. • Secondary Objectives: – A) Phase II: Toxicities associated with TT versus SoC. – B) Phase III: a)PFS b) RR and c) toxicities associated with TT versus SoC. • Exploratory Objectives: A)Additional predictive tumor/blood biomarkers , B) resistance biomarkers at progression C) tissue/ blood repository from patients with refractory SCCA.

Assign treatment Investigational Targeted Therapy Arm by marker Patient Randomization Registration Tumor Consent Collection Treatmen t Genomic Screening <2 weeks Interim Endpoint: PFS Primary Endpoint: OS Genomic NGS/IHC “Pre - screening” (Foundation In selected patients Medicine) Standard of Care Therapy • Organizers: FOCR,NCI-TMSC, FDA, FNIH • Participants: Entire North American Lung Intergroup (SWOG, Alliance, ECOG-Acrin, NRG, NCI-Canada) • Screening: 500-1,000 patients/year • With 4- 6 arms open simultaneously, “hit” rate ~70% in matching a patient with a drug/biomarker arm.